In order to address the goals for this project, we have used several approaches.[unreadable] First are descriptive studies using the Baltimore Longitudinal Study of Aging (BLSA). These studies focus on describing the characteristic losses in muscle strength, muscle mass, and physical functioning that occur with aging by examining the entire adult lifespan and their impact on function and longevity. We have previously demonstrated that declining muscle strength and rate of change of muscle strength are independent contributors to mortality in men when considering age, physical activity and muscle mass. We have further shown that muscle power, and speed of movement are further independent sarcopenic factors that contribute to longevity. The observations suggest that central nervous system processes are contributing to the importance of sarcopenia on longevity. [unreadable] Another important contributor to sarcopenia is inflammation. We asked whether inflammation has changed in the BLSA over the decades and whether this impacted on mortality. We found a longitudinal downward trend in WBC over four decades from the 1960s through the 1990s, which was not accounted for by changes in cigarette smoking. Further, the mortality risk of participants with WBC>6,000/mm3 was higher compared to those with 3,501-6,000 WBC/mm3 and the association remained similar across the decades. The association between WBC and mortality did not substantially change over the 44 years of follow-up. Our findings are compatible with the hypothesis that the secular decline in WBC count contributed to the decline in mortality over the same period, and suggests that levels of inflammation, as assessed by WBC, have been declining over this time period. The impact of this observation on our sarcopenia work is less clear. In some preliminary work, we found no impact of WBC on the relationship of basal metabolic rate with mortality. The two measures appear to have independent effects.[unreadable] In related work, we examined the level of inflammation in relationship to sarcopenic obesity in the InChianti study. Research suggests that inflammatory cytokines produced by adipose tissue, especially visceral fat, accelerate muscle catabolism and contribute to the vicious cycle that initiates and sustains sarcopenic obesity. We tested the hypothesis that obesity and poor muscle strength, hallmarks of sarcopenic obesity, are associated with high circulating levels of proinflammatory cytokines by cross-classifying subjects according to sex-specific tertiles of waist circumference and grip strength and obesity defined as a BMI > or =30 kg/m2. After adjusting for age, sex, education, smoking history, physical activity, and history of comorbid diseases, components of sarcopenic obesity were associated with elevated levels of IL-6, C-reactive protein, IL-1 receptor antagonist, and soluble IL-6 receptor. The observations suggest that global obesity and, to a greater extent, central obesity directly affect inflammation, which in turn negatively affects muscle strength, contributing to the development and progression of sarcopenic obesity. These results suggest that proinflammatory cytokines may be critical in both the development and progression of sarcopenic obesity. [unreadable] The metabolic syndrome (MetS) is a complex of risk factors for type 2 diabetes and cardiovascular disease that includes central obesity. As the prevalence of MetS increases with age, and most dramatically in post-menopausal women, we hypothesized that age related changes in androgens and other hormones might contribute to the development of MetS. We found that in older women, SHBG was negatively associated with MetS independent of confounders, including inflammatory markers and insulin resistance. [unreadable] Insulin-like growth factor-I (IGF-I) is an anabolic hormone primarily involved in skeletal and muscle development during the first two decades of life. Recent studies suggest thhat in older persons, lower IGF-I levels are associated with an increased risk of disability and all-cause and cardiovascular mortality. We compared trends of age-related changes of IGF-I concentration across the adult life span using cross-sectional data collected in the BLSA and the InCHIANTI study. We found that the age-associated decrease in IGF-I was similar across the two different populations.[unreadable] Working with collaborators at the University of Maryland, we are examining genetic contributions related to muscle hypertrophy and strength. We have identified several genes that contribute to the inherited aspects of how much muscle and strength we have. In previous work, we have reported on relationships between IGF-II, IL6 and ciliary neurotrophic facto (CNTF) and muscle strength and muscle mass. Ciliary neurotrophic factor (CNTF) was of particular interest as it is important for neuronal and muscle development, and we had found an association of CNTF with force production via its influence on motor unit size and firing patterns. The observations suggested that genetic influences on nerve and muscle development impact on how the mature nervous system interacts with muscle, and in movement propagation. [unreadable] In related work, we found that longer androgen receptor repeat in exon 1 in men is associated with higher testosterone blood levels and greater levels of fat free mass. In the past year, we examined two genes related to myostatin, a negative regulator of skeletal muscle that plays a key role in muscle development and maintenance. However, DNA sequence variation within this gene has not been consistently associated with skeletal muscle mass nor muscle strength in humans. Follistatin and Activin RIIB (ACVR2B) are two myostatin related genes involved in the regulation/signaling of myostatin. We examined genetic variation in follistatin and ACVR2B to explore associations with skeletal muscle related phenotypes. Women heterozygous for ACVR2B haplotype groups 1 and 2 exhibited significantly less concentric quadriceps muscle strength than women homozygous for haplotype group 2 . No significant association was observed in men. Male but not female carriers of follistatin haplotype group 3 exhibited significantly less total leg FFM than non-carriers. The data indicate that the ACVR2B and follistatin loci may contribute to the inter-individual variation in skeletal muscle mass and strength. [unreadable] We are continuing to examine specific gene associations with muscle strength and muscle mass, to improve understanding of the genetic contributions to sarcopenia and mortality. In the future, we will expand the genetic work, as the BLSA completes a full genome scan. The main question will be to address the relationship between genetic composition and longitudinal changes in muscle strength and muscle mass across the adult life span. [unreadable] The third area of interest has been intervention studies to alter the time course of strength and muscle mass changes. In previous work we demonstrated that the exercise response to resistive training is very similar in young and old subjects. However, while the response to strength training may be similar by age, there are clear differences in muscle responsiveness as represented by gene expression, and body compostion change differences. In the past year, we published a study that assessed age and sex effects on muscle fibre adaptations to heavy-resistance strength training. The observations demonstrated that while both young and elderly individuals respond to strength training and lead to significant increases in strength and type II fibre CSA, age and sex influence specific muscle fibre subtype responses to the training. Further, we have been interested in alternative strategies for exercise intervention for those less inclined to directly exercise including electromyostimulation and a pedometer as a motivational tool to increase activity.